PROJECT SUMMARY/ABSTRACT There is a critical need to identify new antifungal drugs to deal with the rapid increase in invasive fungal pathogens that are resistant to existing antifungal agents. Associate Program 4 will help address this through the collaborative efforts of this ICBG. Specifically, we will couple a unique and highly efficient antifungal discovery platform with the natural product ICBG-created molecular libraries. A successful antimicrobial drug development program requires the ability to rapidly forecast the efficacy and safety of candidate compounds in humans. The goal of this screening and development project is to utilize high-throughput in vitro screens and select infection models with an established track record for projecting human antifungal therapy outcomes to identify novel antimicrobial natural product scaffolds from the ICBG collection. The UW Antimicrobial Testing Facility has extensive experience with clinically relevant in vitro and murine models for the drug-resistant fungal pathogens on which AP5 is focusing. Studies from this facility have frequently been used in FDA submissions. This Facility will perform both the primary, secondary and in vivo assays along with the pharmacological assays needed to select high-value antifungal drugs. In fact, the above UW facility has successfully utilized these tools to discern the clinical efficacy of more than 100 individual compounds, including more than a dozen that have progressed into clinical use. The Facility has designed a natural product compound progression plan to use efficacy and safety in these in vitro screen and clinically relevant in vivo models as an early decision point in lead optimization. AP4 will work closely with the other APs, especially AP2 and AP5, to test promising compounds that advance from AP1, AP2, and AP3 via a logical and progressive screening and development plan.